Several forms of hippocampal synaptic plasticity have been shown to require de novo protein synthesis. N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is the most widely studied cellular model of learning and memory. One form of LTP, long-lasting late-phase LTP (L-LTP), requires both gene transcription and protein translation. Another form of hippocampal synaptic plasticity, metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is of particular interest because it requires rapid translation of preexisting mRNA, bypassing the need for transcription. Do similar signaling pathways couple mGluRs and NMDA receptors to the translation machinery during mGluR-LTD and L-LTP, respectively? This appears to be the case for cap-dependent and 5'TOP translation. In the past several years, several laboratories, including my laboratory, have shown that two key signaling pathways regulate cap-dependent and 5'TOP translation during both mGluR-LTD and L-LTP. These findings have generated much excitement because they were the first demonstration of biochemical regulation of translation during hippocampal synaptic plasticity. We plan to address two critical questions to gain a more complete understanding of the translational control mechanisms operating during hippocampal synaptic plasticity. First, is cap-dependent translation similarly regulated during mGluR-LTD and L-LTP? Second, is eIF2a phosphorylation and are uORF-containing mRNAs differentially translated during mGluR-LTD versus L-LTP? These questions will be addressed by utilizing the powerful multidisciplinary combination of electrophysiological recording techniques, Western blot analyses, direct enzymatic assays, subcellular fractionation, immunocytochemistry, and genetically-modified mice to study mGluR-LTD and L-LTP, as well as learning and memory. The results of our experiments will provide important information concerning the signaling mechanisms that underlie not only synaptic plasticity, but also learning and memory processes. Finally, these studies will generate critical information about the biochemical basis of the alterations in synaptic plasticity that occur in fragile X syndrome and tuberous sclerosis complex, mental retardation syndromes that have altered translation.